This renewal will continue our studies on the CNS consequences of chronic cocaine self-administration in rhesus monkeys. The prefrontal cortex, via its interactions with multiple subcortical structures, is intimately involved in reward evaluation and response selection. Human imaging studies of cortical metabolism indicate distinct altered functional states of prefrontal codex at short and long times following cessation of cocaine. There is also evidence of dysfunctionality of prefrontal cortex in cognitive testing and behavioral studies in human cocaine abusers and non-human primates following chronic cocaine. Our studies will determine how altered prefrontal function is manifested via altered subcodical neurotransmission. Specific Aim 1) Characterize the "normal" mode of prefrontal cortex regulation of dopaminergic and serotonergic neurotransmission in the striatum and basolateral amygdala. The impact of electrical stimulation of three key subregions of the prefrontal cortex (anterior cingulate, orbitofrontal, and dorsolateral) on dopamine (DA) and serotonin (5-HT) release in the mesolimbic and sensorimotor striatum and basolateral amygdala will be determined. Specific Aim 2) Determine whether prefrontal cortex regulation of subcodical DA and 5-HT release has been modified in a time-dependent manner - short term cessation of cocaine. Following a minimum of four months chronic cocaine self-administration, the ability of electrical stimulation of subregions of the prefrontal cortex (anterior cingulate, orbitofrontal, and dorsolateral) to stimulate DA and 5-HT release in mesolimbic and sensorimotor striatum and basolateral amygdala wilt be determined. Each study will be conducted 1 day since last cocaine exposure. Specific Aim 3) Determine whether prefrontal cortex regulation of subcortical DA and 5-HT release has been modified in a time-dependent manner - long term cessation of cocaine. Following four months chronic cocaine self-administration, the ability of electrical stimulation of subregions of the prefrontal cortex (anterior cingulate, orbitofrontal, and dorsolateral) to stimulate DA and 5-HT release in mesolimbic and sensorimotor striatum and basolateral amygdala will be determined. Each study will be conducted 3-4 months since last cocaine exposure.